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Overexpression of the ERK/MAP kinases in oral squamous cell carcinoma
1Department of Pathology, Nara Medical University, Kashihara, Japan. kmishima@yoda.nidr.nih.gov
Abstract:
Mitogen-activated protein kinase (MAPK) is a serine-threonine kinase that is activated by various extracellular stimuli. Extracellular signal-regulated kinases (ERK1 and ERK2), an MAPK subfamily, are activated by many oncogenes, such as ras and raf, and they induce cell proliferation. myc is also an oncogene and one of the targets of ERKs. Mutations of ras and overexpression of myc were found in various human cancers, and ERKs were also reported to play a role in carcinogenesis. In this study, we examined 39 biopsy specimens of oral squamous cell carcinoma (OSCC) and 5 of normal gingival mucosa for the expression of ERK protein and the proliferation marker, MIB-1 (Ki-67 antibody). Thirteen OSCC specimens and five normal gingival biopsies were also examined for the expression of ERKs mRNA by in situ hybridization. Double staining for ERKs and MIB-1 was also performed. Histologically, 18 patients (46%) were diagnosed with well-differentiated SCC, 17 (44%) with moderately differentiated SCC, and 4 (10%) with poorly differentiated SCC. The histologic grade correlated with the MIB-1 index. The localization of ERK1 was similar to that of ERK2. Positive signals for ERK proteins were localized in superficial keratinocytes in normal gingival mucosa, whereas these mRNAs were weakly positive in the basal and spinous layer. Basal and suprabasal cells were positive for MIB-1. In well-differentiated and moderately differentiated OSCC, positive signals for ERK mRNA and proteins were found at higher levels than in normal gingival mucosa in keratotic cells around cancer pearls. Some cells showed positive signals for ERKs and MIB-1. Furthermore, most cancer cells in poorly differentiated SCC were positive for both ERK and MIB-1. The histologic grade was statistically related to the percentage of cells positive for both ERK and MIB-1. This suggested that ERKs might be related to proliferation in OSCC.
Insights
Extracellular signal-regulated kinases (ERKs) are linked to cell proliferation in oral squamous cell carcinoma (OSCC). Higher ERK expression correlates with poorly differentiated OSCC, suggesting a role in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Mitogen-activated protein kinase (MAPK) pathways regulate cellular responses to stimuli.
- Extracellular signal-regulated kinases (ERK1/ERK2) are key components of the MAPK pathway, implicated in cell proliferation and oncogenesis.
- ERK activation by oncogenes like ras and raf, and its role as a target of myc, highlight its significance in cancer.
Purpose of the Study:
- To investigate the expression of Extracellular signal-regulated kinases (ERKs) in oral squamous cell carcinoma (OSCC).
- To correlate ERK expression with the proliferation marker MIB-1 (Ki-67) and histological grade in OSCC.
- To explore the potential role of ERKs in the proliferation of OSCC cells.
Main Methods:
- Analysis of 39 OSCC biopsy specimens and 5 normal gingival mucosa samples.
- Assessment of ERK protein and ERK mRNA expression using immunohistochemistry and in situ hybridization.
- Evaluation of the proliferation marker MIB-1 (Ki-67) and double staining for ERKs and MIB-1.
- Correlation of ERK expression and MIB-1 index with histological differentiation of OSCC.
Main Results:
- ERK1 and ERK2 protein and mRNA expression were detected in both normal gingival mucosa and OSCC tissues.
- ERK expression was generally higher in OSCC compared to normal mucosa, particularly in keratotic cells and poorly differentiated tumors.
- A significant correlation was observed between histological grade, MIB-1 index, and the percentage of cells positive for both ERK and MIB-1.
- Positive signals for ERKs and MIB-1 were frequently found together in cancer cells, especially in poorly differentiated OSCC.
Conclusions:
- ERK expression is elevated in oral squamous cell carcinoma.
- ERK signaling is associated with increased cell proliferation in OSCC, as indicated by its co-localization with the MIB-1 proliferation marker.
- ERKs may play a significant role in the proliferation and progression of oral squamous cell carcinoma.